The goal of this research is to develop new methods for the design and synthesis of Type-III Peptidomimetic inhibitors of aspartic proteases. A Type-III mimetic, is an organic structure, distinctly different in shape and atom type from a peptide substrate, that binds so as to complement the local topography in the enzyme active site. These are considered likely to lead efficiently to orally bioavailable enzyme inhibitors. Model studies with pepsin and R. Chinensis pepsin will be continued by creating potential candidates for synthesis by applying the structure-generating program, GrowMol, to two different classes of enzyme-inhibitor complexes: (1) those formed from tight-binding transition-state analogs bound to the target enzyme; and (2) those formed from weaker binding inhibitors bound to a destabilized enzyme. Of the many potential synthetic targets generated, Beilstein's CrossFire is used to identify synthetically accessible templates or core structures from which to build the peptidomimetic. These are further refined by the chemist, synthesized, assayed against the target enzyme and when active, their binding mode to the enzyme will be determined by X-ray crystrallography. New strategies for the Design of Protease Inhibitors will result and the goal is to find ways to design Type-III peptidomimetic inhibitors directly from the structures of peptide inhibitors bound to the target enzyme. These strategies will be applied to two clinically important aspartic proteases, HIV protease and plasmepsin II.